For a patient with insomnia, which off‑label medication is more appropriate: trazodone or mirtazapine?

Trazodone vs Mirtazapine for Insomnia

For off-label treatment of insomnia, mirtazapine is the preferred choice over trazodone, based on the American Academy of Sleep Medicine's explicit recommendation against trazodone and the superior efficacy profile of mirtazapine at low doses.

Why Mirtazapine is Preferred

Mirtazapine demonstrates superior efficacy for insomnia treatment, particularly at low doses (7.5–15 mg), with response rates exceeding 86% in patients with chronic insomnia. 1 The American Academy of Sleep Medicine positions mirtazapine as a first-line sedating antidepressant option for patients with depression and comorbid insomnia, alongside other agents, with the choice guided by side effect profile and patient-specific factors. 2

Optimal Dosing Strategy

• Start mirtazapine at 7.5 mg at bedtime (maximum 30 mg), as this low dose corresponds to the highest percentage of responders (52.5%) and provides strong sedation through histamine H₁-receptor antagonism. 2, 1
• Lower doses (7.5–15 mg) achieve 100% response rates compared to only 53.84% with higher doses (15–30 mg), demonstrating a paradoxical inverse dose-response relationship where lower doses are more sedating. 1
• Mirtazapine promotes sleep, appetite, and weight gain, which may be beneficial in patients with poor appetite but requires monitoring in those concerned about weight. 2

Pharmacologic Advantages

• Mirtazapine has minimal anticholinergic effects compared to tricyclics, making it safer in elderly patients. 2
• The medication exhibits very weak muscarinic anticholinergic activity and minimal cytochrome P450 inhibition, reducing drug-drug interaction risks. 3
• Sustained efficacy over long-term use (≥3 months) without tolerance development has been demonstrated in clinical practice. 1

Why Trazodone Should Be Avoided

The American Academy of Sleep Medicine explicitly recommends against trazodone for sleep onset or sleep maintenance insomnia, citing minimal benefit and harms that outweigh benefits. 2, 3

Evidence Against Trazodone

• Trazodone produces only a ~10-minute reduction in sleep latency and ~8 minutes reduction in wake after sleep onset, with no improvement in subjective sleep quality. 2, 3
• Adverse events occur in ~75% of older adults (headache ~30%, somnolence ~23%), compared to ~65% on placebo. 3
• Despite widespread off-label use, trazodone lacks robust efficacy data for primary insomnia, with the AASM issuing a weak recommendation against its use based on a single trial showing clinically insignificant improvements. 3
• Higher doses (100–150 mg) show only 42.85% response rates compared to 100% at lower doses (25–75 mg), but even at optimal dosing, trazodone remains inferior to mirtazapine. 1

Head-to-Head Comparison Data

A retrospective comparative study of 79 patients with chronic insomnia found no significant difference in response rates between trazodone (87.87%) and mirtazapine (86.95%), but mirtazapine achieved these results at lower doses with better tolerability. 1

• Both medications were efficacious in >60% of patients regardless of sex, age, or association with dysthymic disorder. 1
• Mirtazapine's minimum effective dose (7.5 mg) is substantially lower than trazodone's (25 mg), reducing side effect burden. 1
• Long-term administration (≥3 months) showed sustained efficacy for both drugs, but mirtazapine's superior safety profile and guideline support make it the preferred choice. 1

Treatment Algorithm

1. Initiate Cognitive Behavioral Therapy for Insomnia (CBT-I) first for all patients with chronic insomnia, as it provides superior long-term efficacy compared to medications alone. 2, 3

2. If pharmacotherapy is needed after CBT-I initiation:

   • Start mirtazapine 7.5 mg at bedtime for patients with or without comorbid depression/anxiety. 2, 1
   • Titrate to 15 mg after 1–2 weeks if insufficient response, avoiding doses >30 mg as higher doses paradoxically reduce sedation. 2, 1

3. Monitor after 2–4 weeks for sleep-onset latency, total sleep time, nocturnal awakenings, daytime functioning, and adverse effects (weight gain, morning sedation). 3

4. If mirtazapine fails or is contraindicated, consider FDA-approved first-line agents such as low-dose doxepin (3–6 mg) for sleep maintenance or eszopiclone (2–3 mg) for combined sleep onset and maintenance, rather than switching to trazodone. 2, 3

Special Population Considerations

• Elderly patients: Mirtazapine has minimal anticholinergic effects compared to tricyclics, making it safer in this population, though weight gain and fall risk require monitoring. 2
• Patients with comorbid depression: Mirtazapine addresses both insomnia and mood symptoms simultaneously at therapeutic doses (15–45 mg). 2, 4
• Patients concerned about weight gain: Consider alternative agents, as mirtazapine promotes appetite and weight gain through histamine receptor antagonism. 2, 4

Critical Safety Warnings

• Avoid combining mirtazapine with multiple sedating agents (benzodiazepines, Z-drugs), as polypharmacy markedly increases risks of respiratory depression, cognitive impairment, and falls. 3
• Trazodone carries significant risks including drowsiness, dizziness, and in rare cases priapism, with limited efficacy data to justify these risks for insomnia treatment. 4, 5
• Both medications should be used at the lowest effective dose for the shortest duration, with regular reassessment every 4–8 weeks to determine continued need. 2, 3

Common Pitfalls to Avoid

• Prescribing trazodone based on perceived safety rather than evidence – guideline bodies explicitly recommend against this practice despite its widespread off-label use. 2, 3
• Using higher doses of mirtazapine (>15 mg) for insomnia – paradoxically reduces sedation due to increased noradrenergic activation. 1
• Failing to implement CBT-I alongside medication – behavioral therapy provides more durable benefits than pharmacotherapy alone. 2, 3
• Continuing either medication long-term without periodic reassessment – both should be tapered when conditions allow, using CBT-I to facilitate discontinuation. 2, 3